During the course of a lifetime humans encounter a large number of viruses, some of which are eradicated, and some of which remain as chronic, life-long infections. Previous infections can impact the way in which the immune system deals with subsequent infections and we have investigated this issue using a mouse model in which the animals are either acutely or chronically infected with one virus before infection with a different virus. We found that mice infected with lactate dehydrogenase-elevating virus (LDV) have dampened T cell responses to subsequent infection with Friend retrovirus. These studies led to investigation of how LDV caused that effect. We found that acute LDV infection activated plasmacytoid dendritic cells and caused them to secrete alpha interferon in a TLR-7-dependent manner. The alpha interferon caused a transient, partial, polyclonal activation of both CD4+ and CD8+ T cells and also B cells. Associated with this was a failure of dendritic cells to mature and present antigens to T cells. Previous studies in our lab showed that regulatory T cells (Tregs) suppressed anti-viral CD8+ T cell responses in mice chronically infected with Friend retrovirus. New collaborative studies with the Kassiotis lab revealed that Tregs also provided benefiical effects in protecting against overactive CD4+ T cell responses that could cause an autoimmune type disorder in the bone marrow. Studies on FV-specific CD4+ T cells also demonstrated that they possessed a direct antiviral effect separate from their helper function.